The role of cardiac stem cells in response to cardiac injury. (360G-Wellcome-082002_Z_07_Z)

While the response to imposed cardiac stresses (e.g. afterload due to hypertension) have traditionally been understood in terms of the manifest morphological changes (e.g. hypertrophy and dilatation), the molecular determinants of these distinct morphological states are increasingly well understood the molecular level. Genomic analyses have yielded a number of potential key nodes that may determine or modify the pattern and timing of these transitions. Hypertrophic cardiomyopathy (HCM) represents a particularly good model in which to study these changes, since its monogenic nature of inheritance ensures that the inciting influence to hypertrophy and even to dilatation is "pure". It is increasingly recognized that in HCM, energy deficiency appears to be the key inciting influence driving these changes. Although the molecular correlates and in some cases determinants of compensatory morphological changes have been described, the cellular changes mediating these transitions have been less forthcoming. A number of studies have implicated resident cardiac stem cells as critical determinants of compensatory morphological changes. We propose to use human and animal models of HCM to assess the contribution of cardiac stem cells to pathological hypertrophy and dilatation. Not only do we aim to dissect out the role of stem cells in HCM, but will subsequently intend to use existing animal models of HCM to assess the role of stem cells in acquired causes of cardiomyopathy and heart failure. Ultimately this model may prove influential in understanding basic stem cell biology but may also prove a dominant model in which to assess cardiac interventions intend to promote endogenous cardiac stem cells therapeutically.